The drug diltiazem chemically is 1,5-benzothiazepin-4 (5H)one,3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyl phenyl). Diltiazem is therapeutically indicated as a calcium ion influx inhibitor, which activity is known also as calcium channel blocker and as calcium antagonist.
The biological activity of diltiazem is its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscles. The drug diltiazem and its pharmaceutically acceptable salts is a potent dilator of coronary arteries, both epicardial and subendocardial. Diltiazem exhibits the ability to increase exercise tolerance due to diltiazem's ability to reduce myocardial oxygen demand. This biological activity is effected by a reduction in the heart rate and the systemic blood pressure in submaximal and maximal exercise work loads. These activities indicate diltiazem is useful for the management of myocardial ischemia and angina due to coronary artery spasm.
Presently diltiazem is administered by conventional non-rate controlled tablets in single doses of 30 to 120 milligrams taken three or four times a day. This administration results in detectable plasma levels within about 30 to 60 minutes and peak levels in about two to three hours after diltiazem administration. The therapeutic level for diltiazem is about 50 to 200 nanograms per milliliter of plasma, as reported in Physician's Desk Reference, 42nd Ed., pp. 1221-22, (1988).
In the light of the above presentation, it will be appreciated by those versed in the pharmaceutical dispensing art, to which this invention pertains, that a pressing need exists for a dosage form that delivers diltiazem at a controlled rate to a patient in critical need of cardiovascular diltiazem therapy. The pressing need exists also for an oral dosage form that delivers diltiazem at a controlled rate and at a constant dose per unit time over a prolonged period of time. The need exists for a rate controlled dosage form for the gastrointestinal delivery of diltiazem for obtaining diltiazem's beneficial hemodynamic effects by a dosage form that is free of fluid wash-out of diltiazem from the dosage form and delivers it at a controlled rate that is substantially independent of the variable environment of the gastrointestinal tract. It will be appreciated further by those versed in the dispensing art that such a novel and unique dosage form that can administer diltiazem at a rate controlled dose over time and, simultaneously, provide cardiovascular therapy would represent both an advancement and a valuable improvement in the medical art.